There are approximately 275,000 skeletal defects a year reported in the U.S. general population that require bone graft procedures to achieve union. In addition, there is a need to provide care to the increasing number of soldiers and Marines suffering from critical head injuries caused by bomb blasts, munitions, serious falls and vehicle accidents to those engaged in the Iraq conflict. The research described in this proposal is directed towards this clinical problem of repairing critical-sized cranial defects. Critical sized cranial defects are often the result of bone loss due to the removal of primary and metastatic tumors, bone loss after skeletal trauma, or as a result of congenital deformity. The ultimate surgical goal is to repair the defect by implantation of a functional, biodegradable, biocompatible, bioactive scaffold that will illicit bone regeneration and over time fully integrate with the host bone. The overall goal of this research is to develop methods to accurately fabricate custom-designed polypropylene fumarate) (PPF) porous scaffolds suitable for bone regeneration and render those scaffolds bioactive by culturing in a perfusion bioreactor in the presence of rat marrow stromal cells (MSCs) and osteogenic supplemented media. To accomplish this goal, this project will be divided into three specific aims: 1) design and manufacture a perfusion bioreactor capable of perfusing custom porous scaffolds;2) design and manufacture porous scaffolds suitable for bone regeneration in the biocompatible polymer PPF using the layered manufacturing technology stereolithography (SL);and 3) render the PPF porous scaffolds bioactive.The first section of this study will focus on the design and manufacture of a perfusion bioreactor with interchangeable cassettes suitable for the location of custom designed scaffolds. PPF will be synthesized with molecular weights of 800-1,000 Da and 1,800-2,000 Da following previously published procedures. Three-dimensional CAD will be used to design custom porous scaffolds with accurately controlled external and internal highly porous, interconnected architecture. Scaffolds will be manufactured using stereolithography, seeded with rat MSCs, and incubated in perfusion bioreactors for 4, 8 and 12 days. The degree of bioactivity will be determined by ELISA protein assays, and degree of calcium deposition. This research will develop manufacturing and biological strategies to produce bioactive patient-specific scaffolds for the repair of maxiliofacial bone defects.